Prolonged-release multimicroparticulate oral pharmaceutical form

Abstract

Modified-release multimicroparticulate pharmaceutical form capable of maintaining the modified release of the active principle in an alcoholic solution and of resisting attempts at misuse.

What is claimed is: 
     
       1. An oral pharmaceutical form resisting dose dumping in the presence of alcohol, wherein said pharmaceutical form comprises:
 i) coated microparticles comprising at least active principle (AP) and providing modified release of said AP; 
 ii) at least one viscosity agent V; and 
 iii) an agent D selected from the group consisting of: methylcellulose: hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxy(alkyl)celluloses and salts thereof, and mixture thereof; 
 wherein said AP is selected from the group consisting of: opiates, anxiolytics, benzodiazepines, anorexigens, antidepressants, antiepileptics, antiparkinsonian agents, barbiturates, hypnotics, neuroleptics, psychostimulants, psychotropic agents, amphetamines and mixtures thereof; 
 wherein the coated microparticles of AP comprise a coating layer R; 
 wherein said coating layer R ensures the modified release of the AP and simultaneously confers, on the coated microparticles of AP, resistance to crushing; 
 wherein said coating layer R represents 30-60% of the total mass of the coated microparticles of AP; 
 wherein said coating layer R comprises:
 at least one film-forming (co)polymer A1 which is insoluble in the fluids of the digestive tube, representing between 60% and 90% by weight relative to the weight of the coating layer R; 
 at least one (co)polymer A2 which is soluble in the fluids of the digestive tubes, representing between 5% and 40% by weight relative to the weight of the coating layer R; and 
 at least one plasticizer A3, representing between 1% and 30% by weight relative to the weight of the coating layer R; 
 
 wherein the viscosity agent V is in the form of microparticles distinct from the microparticles of AP, 
 wherein the agent D is present in a mixture with the coated microparticles of AP, in the form of microparticles distinct from the microparticles of AP, or is one of the outer constituents of a monolithic form. 
 
     
     
       2. The pharmaceutical form of  claim 1 , further comprising at least one quenching agent Q in the form of microparticles distinct from the microparticles of AP. 
     
     
       3. The pharmaceutical form of  claim 1 , in which the agent D is present in the mixture with the coated microparticles of AP, in a proportion of 0.5% to 30% w/w of the total mass of the unit form. 
     
     
       4. The pharmaceutical form as claimed in  claim 1 , in which the coating layer R further comprises:
 at least one surfactant and/or one lubricant and/or mineral filler and/or organic filler A4, representing less than 40% by weight relative to the weight of the coating layer R. 
 
     
     
       5. The pharmaceutical form as claimed in  claim 1 , in which:
 A1 is selected from the group consisting of: water-insoluble derivatives of cellulose, acrylic polymers, poly(vinyl acetate)s, and mixtures thereof; 
 A2 is selected from the group consisting of: nitrogenous (co)polymers, water-soluble derivatives of cellulose, polyvinyl alcohols (PVAs), polyalkylene oxides, polyethylene glycols (PEGs), and mixtures thereof; 
 A3 is selected from the group consisting of: cetyl alcohol esters, glycerol and esters thereof, phthalates, citrates, sebacates, adipates, azelates, benzoates, plant oils, fumarates, malates, oxalates, succinates, butyrates, cetyl alcohol esters, malonates, castor oil and mixtures thereof. 
 
     
     
       6. The pharmaceutical form as claimed in  claim 5 , in which:
 A1 is selected from the group consisting of water-insoluble derivatives of cellulose, 
 A2 is selected from the group consisting of: polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVPs) and poly-N-vinyllactams, water-soluble derivatives of cellulose, polyethylene glycols (PEGs), and mixtures thereof; 
 A3 is selected from the group consisting of: triethyl citrate, dibutyl sebacate, plant oils, castor oil and mixtures thereof. 
 
     
     
       7. The pharmaceutical form of  claim 1 , wherein the coating layer (R) comprises A1, A2, and A3 in the following proportions (in % by weight, based on the total weight of the coating):
 for A1: 60≦m≦80, 
 for A2: 5≦m≦25, 
 for A3: 5≦m≦15. 
 
     
     
       8. The pharmaceutical form as claimed in  claim 1 , in which at least one viscosity agent V is chose from viscosity agents which are soluble in at least one of the following extraction solvents: water, alcohol, ketones, and mixtures thereof. 
     
     
       9. The pharmaceutical form as claimed in  claim 1 , in which the viscosity agent V is selected from the group consisting of: poly(meth)acrylic acid and poly(meth)acrylic-based compounds, polyalkylene glycols, or polyalkylene oxides, polyvinylpyrrolidones, gelatins, sodium alginate, pectins, guars, xanthans, carrageenans, gellans, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and mixtures thereof. 
     
     
       10. The pharmaceutical form as claimed in  claim 9 , in which the viscosity agent V is selected from the group consisting of: polyalkylene oxides, xanthans, hydroxypropylcellulose, and mixtures thereof. 
     
     
       11. The pharmaceutical form of  claim 8 , in which the amount of agent V in the pharmaceutical form is adjusted so as to render the viscosity of 2.5 ml of the extraction solvent greater than or equal to 100 mPa·s. 
     
     
       12. The pharmaceutical form of  claim 1 , in which the viscosity agent V is a polyoxyethylene having a molecular weight of 1 million g/mol to 8 million g/mol. 
     
     
       13. The pharmaceutical form as claimed in  claim 2 , in which the quenching agent Q comprises a salt, which contains ions capable of forming a complex with salt of AP extracted in solution. 
     
     
       14. The pharmaceutical form as claimed in  claim 13 , in which the ions of the quenching Q are organic ions of polarity opposite to that of the AP in solution, and which form a complex with the salt of AP extracted in solution. 
     
     
       15. The pharmaceutical form of  claim 13 , in which the quenching agent Q is present in a first phase separate from at least a second phase, said second phase containing at least one salt of AP. 
     
     
       16. The pharmaceutical form as claimed in  claim 2 , in which microparticles of AP and microparticles of quenching agent Q have a similar size distribution and a similar density and are impossible to separate from one another by sifting. 
     
     
       17. The pharmaceutical form as claimed in  claim 14 , in which the ion of polarity opposite to that of the AP in solution is an organic anion. 
     
     
       18. The pharmaceutical form of  claim 13 , in which the quenching agent Q comprises a salt selected from the group consisting of: anionic organic salts, anionic polymers, monovalent or polyvalent salts, saponified fatty acids, polyamino acids, proteins, peptides, and mixtures thereof. 
     
     
       19. The pharmaceutical form as claimed in  claim 13 , in which the ion capable of forming a complex with salt of AP extracted in solution is a metal cation, an organic cation, or a mixture thereof. 
     
     
       20. The pharmaceutical form of  claim 13 , in which the quenching agent Q comprises a salt selected from the group consisting of: cationic salts, organic cationic salts, cationic polymers, polyamino acids, proteins, peptides; and mixtures thereof. 
     
     
       21. The pharmaceutical form of  claim 13 , in which the quenching agent Q is an ion exchange resin. 
     
     
       22. The pharmaceutical form as claimed in  claim 21 , in which the quenching agent Q is a derivative of a styrene/divinylbenzene copolymer. 
     
     
       23. The pharmaceutical form as claimed in  claim 21 , in which the quenching agent Q is a derivative of a sulfonic styrene/divinylbenzene copolymer. 
     
     
       24. The pharmaceutical form as claimed in  claim 21 , in which the quenching agent Q is a derivative of styrene/divinylbenzene copolymer bearing quaternary ammonium functions. 
     
     
       25. The pharmaceutical form as claimed in  claim 21 , in which the quenching agent is a crosslinked copolymer of methacrylic acid and of divinylbenzene, or a salt thereof. 
     
     
       26. The pharmaceutical form as claimed in  claim 21 , in which the ion exchange resin is a phenolic polyamine. 
     
     
       27. The pharmaceutical form  claim 13 , in which the quenching agent Q is chosen from: anionic organic salts, cationic organic salts and strongly acidic cation exchange resins or strongly basic anion exchange resins, depending on the polarity of the AP. 
     
     
       28. The pharmaceutical form of  claim 13 , in which the amount of quenching agent is adjusted so as to complex all or part of the dose of AP contained in the unit form. 
     
     
       29. The pharmaceutical form of  claim 1 , comprising at least one excipient not contained in or supported by the microparticles of AP, said excipient contributing to the resistance of crushing of the coated microparticles of AP and selected from the group consisting of calcium stearate, glyceryl behenate, glyceryl palmitostearate, magnesium oxide, polyalkylene glycols, polyvinyl alcohol, sodium benzoate, stearic acid, corn starch, talc, colloidal silica, zinc stearate, magnesium stearate, stearyl fumarate, and mixtures thereof. 
     
     
       30. The pharmaceutical form of  claim 2 , comprising:
 a) an AP, at least part of which is contained in microparticles individually coated with a coating R which ensures the modified release of the AP and simultaneously confers resistance to crushing of the coated microparticles of AP, where for each constituent A1, A2 and A3 of the coating layer R, its mass m (as % of the total mass of the coating R) bears out: 
 for A1: 60≦m≦90, 
 for A2: 5≦m≦40, 
 for A3: 1≦m≦30, 
 b) at least one agent D which is present in a proportion of 0.5% to 30% w/w, of the total mass of the unit form; 
 c) at least one viscosity agent V present in a proportion of 2 to 400 mg, 
 d) at least one quenching agent Q, the amount of which is adjusted in order to trap all or part of the dose of AP contained in the unit form, the quenching agent Q being included in a separate phase distinct from the phase containing the AP. 
 
     
     
       31. The pharmaceutical form as claimed in  claim 30 , comprising microparticles of viscosity agent V and coated microparticles of AP, said microparticles having a similar size distribution and a similar density and being impossible to separate from one another by sifting. 
     
     
       32. The pharmaceutical form of  claim 30 , in which the coating layer R contains the following components:
 A1 selected from the group consisting of: 
 water-insoluble derivatives of cellulose, 
 A2 selected from the group consisting of: 
 nitrogenous (co)polymers, water-soluble derivatives of cellulose, polyethylene glycols (PEGs), and mixtures thereof; 
 A3 selected from the group consisting of: 
 triethyl citrate, dibutyl sebacate, plant oils, castor oil, and mixtures thereof. 
 
     
     
       33. The pharmaceutical form of  claim 30 , in which the viscosity agent V is chosen from: polyalkylene oxides, xanthans, cellulose derivatives and mixtures thereof. 
     
     
       34. The pharmaceutical form of  claim 30 , in which the quenching agent Q is selected from the group consisting of: anionic organic salts, cationic organic salts and ion exchange resins. 
     
     
       35. The pharmaceutical form of  claim 30 , in which the quenching agent Q is chosen from: strongly acidic cation exchange resins and mixtures thereof, when the AP is cationic; strongly basic anion exchange resins and mixtures thereof, when the AP is anionic. 
     
     
       36. The pharmaceutical form of  claim 30 , which is in a tablet form, comprising:
 a) an AP, at least part of which is contained in microparticles individually coated with a coating R which ensures the modified release of the AP and simultaneously confers resistance to crushing of the coated microparticles of AP, where, for each constituent A1, A2 and A3 of the coating layer R, its mass m (as % of the total mass of the coating R) bears out: 
 for A1: 60≦m≦90, 
 for A2: 5≦m≦40, 
 for A3: 1≦m≦30, 
 b) at least one agent D is present as a mixture with the microparticles in a proportion of 1% to 30% w/w of the total mass of the unit form; 
 c) at least one viscosity agent V contained in microparticles distinct from the microparticles of AP, in a proportion of 2 to 400 mg-per unit form; 
 d) at least one quenching agent Q contained in microparticles distinct from the microparticles of AP and of viscosity agent; the amount of quenching agent being adjusted in terms of ionic charge, in order to trap all or part of the dose of AP contained in the unit form; 
 e) compression excipients. 
 
     
     
       37. The pharmaceutical form of  claim 30 , which is in a gelatin capsule unit form, comprising:
 a) an AP, at least part of which is contained in microparticles individually coated with a coating R which ensures the modified release of the AP and simultaneously confers resistance to crushing of the coated microparticles of AP, and where, for each constituent A1, A2 and A3 of the coating layer R, its mass m (as % of the total mass of the coating R) bears out: 
 for A1: 60≦m≦90, 
 for A2: 5≦m≦40, 
 for A3: 1≦m≦30, 
 b) at least one agent D which is present in a proportion of 0.5% to 20% w/w, of the total mass of the unit form; 
 c) at least one viscosity agent V contained in microparticles distinct form the microparticles of AP, in a proportion of 2 to 400 mg, per unit form; 
 d) at least one quenching agent Q contained in microparticles distinct from the microparticles of AP and of viscosity agent; the amount of quenching agent being adjusted in terms of ionic charge, in order to trap all or part of the dose of AP contained in the unit form. 
 
     
     
       38. The pharmaceutical form of  claim 37 , comprising coated microparticles of AP, and also microparticles of viscosity agent V and/or microparticles of quenching agent Q, said microparticles having a similar size distribution and a similar density and being impossible to separate form one another by sifting. 
     
     
       39. The pharmaceutical form of  claim 1 , wherein the coated microparticles of AP have a volume-average diameter of less than or equal to 1000 μm. 
     
     
       40. The pharmaceutical form of  claim 1 , comprising at least:
 microparticles of AP coated with a coating and resistant to crushing; an ion exchange resin; 
 polyoxyethylene; methylcellulose. 
 
     
     
       41. The pharmaceutical form of  claim 1 , comprising at least: microparticles of AP coated with a coating and resistant to crushing; an ion exchange resin; polyoxyethylene; methylcellulose; hydroxyethylcellulose. 
     
     
       42. The pharmaceutical form as claimed in  claim 37 , which is in the form of a gelatin capsule coated with an agent D based on sodium carboxymethylcellulose. 
     
     
       43. The pharmaceutical form as claimed in  claim 37 , which is in the form of a gelatin capsule coated with an agent D based on hydroxyethylcellulose. 
     
     
       44. The pharmaceutical form of  claim 1 , comprising modified-release microparticles of AP and immediate-release microparticles of AP. 
     
     
       45. The pharmaceutical form of  claim 1 , comprising a plurality of populations of coated microparticles of AP, said populations differing from one another by virtue of their release kinetics and/or by virtue of the AP that they contain. 
     
     
       46. The pharmaceutical form  claim 1 , in which the active principle is chosen from the group consisting of: acetorphine, acetyl-alpha-methylfentanyl, acetyldihydrocodeine, acetylmethadol, alfentanil, allylprodine, alpha-cetylmethadol, alphameprodine, alphaprodine, alphamethadol, alpha-methylfentanyl, alphamethylthiofentanyl, anileridine, butorphanol, benzethidine, benzylmorphine, beta-hydroxyfentanyl, beta-hydroxymethyl-3-fentanyl, beta-cetylmethadol, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, dioxaphetyl butyrate, clonitazene, cyclazocine, cannabis, codeine, coca, cocaine, codoxime, dezocine, dimenoxadol, dipipanone, desomorphine, dextromoramide, dextropropoxyphene, diampromide, diethylthiambutene, difenoxin, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, diphenoxylate, dipipanone, drotebanol, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, ethylmethylthiambutene, ethylmorphine, etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone, hydromorphinol, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, lofentanil, levomethorphan, levomoramide, levophenacylmorphan, levorphanol, meptazinol, meperidine, metazocine, methadone, methyldesorphine, methyldihydromorphine, methylphenidate, methyl-3-thiofentanyl, methyl-3-fentanyl, metopon, moramide, morpheridine, morphine, myrophine, nalbuphine, narceine, norlevorphanol, normethadone, nalorphine, normorphine, nicocodine, nicodicodine, nicomorphine, noracymethadol, norcodeine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, phenadoxone, phenoperidine, promedol, properidine, propiram, propoxyphene, parafluorofentanyl, pentazocine, pethidine, phenampromide, phenazocine, phenomorphan, phenoperidine, pholcodine, piminodine, piritramide, proheptazine, racemethorphan, racemoramide, racemorphan, remifentanil, sufentanil, thebacone, thebaine, thiofentanyl, tilidine, trimeperidine, tramadol, and the pharmacologically acceptable salts, esters, hydrates, polymorphs and isomers thereof, and mixtures thereof. 
     
     
       47. The pharmaceutical form of  claim 1 , in which the AP is selected from the group consisting of oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride, hydromorphone hydrochloride, hydrocodone hydrochloride and tramadol hydrochloride. 
     
     
       48. A method for obtaining a pharmaceutical form of  claim 1 , in several steps comprising:
 a) preparing uncoated microparticles of AP by:
 extrusion/spheronization of AP; 
 wet granulation of AP; 
 compacting of AP; 
 spraying of AP, onto a neutral support or; 
 sifting of powder or crystals of AP; 
 
 b) preparing reservoir microparticles of AP by:
 spraying, in a fluidized air bed, a solution or dispersion containing A1, A2 and A3 onto the uncoated microparticles of AP; 
 
 c) preparing the final form of the drug by:
 granulation or extrusion/spheronization of the reservoir microparticles of AP with agents D, V and Q for formulation in gelatin capsules or sachets; 
 mixing of reservoir microparticles of AP with one or more agent(s) D, V and Q and pharmaceutically acceptable excipients, so as to obtain a tablet; 
 formulation in gelatin capsules, of reservoir microparticles of AP, of V and of Q, wherein said gelatin capsules are coated with one or more agent(s) D; or 
 formulation in sachets, of reservoir microparticles of AP, of V and of Q with one or more agent(s) D and pharmaceutically acceptable excipients. 
 
 
     
     
       49. The pharmaceutical form of  claim 1 , wherein the coating layer R represents a fraction by mass Tp, expressed as a percentage by weight on a dry basis relative to the total weight of the microcapsules, is between 40-60%. 
     
     
       50. The pharmaceutical form of  claim 1 , wherein the coating layer R represents a fraction by mass Tp, expressed as a percentage by weight on a dry basis relative to the total weight of the microcapsules, is between 45-55%. 
     
     
       51. The pharmaceutical form as claimed in  claim 4 , wherein the coating layer R further comprises less than 40% by weight of A4 relative to the weight of the coating layer R, wherein A4 is selected from the group consisting of: polyoxyethylenated oils, polyethylene oxide-polypropylene oxide copolymers (poloxamer), polyoxyethylenated sorbitan esters, polysorbates, stearates, and mixtures thereof. 
     
     
       52. The pharmaceutical form as claimed in  claim 4 , in which A4 is selected from the group consisting of: anionic surfactants, nonionic surfactants, stearates, stearyl fumarates, glycerol behenates, talc, colloidal silica, titanium oxide, magnesium oxide, bentonite, microcrystalline cellulose, kaoline, aluminum silicate, and mixtures thereof. 
     
     
       53. The pharmaceutical form as claimed in  claim 52 , in which A4 is selected from the group consisting of: anionic surfactants. 
     
     
       54. The pharmaceutical form of  claim 4 , in which A4 represents less than 20% by weight relative to the weight of the coating layer R. 
     
     
       55. The pharmaceutical form of  claim 1 , wherein said core comprising said AP is a matrix granule containing said AP and other pharmaceutically acceptable excipients or is a neutral support particle coated with at least one layer comprising said AP.